In the lymphoma forward mutation assay, there are chemicals which show a mutagenic' effect only at highly toxic doses. This leads to the concern that the observed mutagenicity may be due to "selection" of the spontaneous mutants due to a greater chemical toxicity to wild-type over mutants cells. Studies to examine this problem can involve isolating wild-type and mutant clones and determining the relative toxicity of the chemical to wild-type and mutant cells. However, this method is indirect, i.e., the clones tested may not be representative of the cellular response in the mutation assay. We are presently developing a direct technique of measuring mutant selection due to differential toxicity, conducted in the experiment used to test the chemical for mutagenic activity. Using this technique, we have shown that certain nucleotide analogs select for as well as induce mutants. These studies are being extended to examine other compounds which only show mutagenic activity at doses which also cause high toxicity.